Pharmaceutical compositions containing abiguanide-glitazone combination

ABSTRACT

The present invention relates to an orally administered pharmaceutical composition that is a combination of two or more antidiabetic agents in which one of the antidiabetic agents is present in an extended release form and the other antidiabetic agent is present in an immediate release form.

FIELD OF THE INVENTION

The present invention relates to an orally administered pharmaceuticalcomposition that is a combination of two or more antidiabetic agents inwhich one of the antidiabetic agents is present in an extended releaseform and the other antidiabetic agent is present in an immediate releaseform.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a metabolic disorder characterized by hyperglycemiaand insulin resistance, and is often associated with other conditionssuch as obesity, hypertension, hyperlipidemia, cardiovascular disease,retinopathy, neuropathy, and nephropathy. The disease is progressive innature but often can be controlled initially by diet alone, although itgenerally requires treatment with drugs, such as sulfonylureas, andinjections of exogenous insulin. Two major forms of diabetes mellitusare now recognized: Type I and Type II. Type I diabetes, orinsulin-dependent diabetes, is the result of an absolute deficiency ofinsulin, the hormone that regulates glucose utilization; patients withType I diabetes are dependent on exogenous insulin for survival. Type IIdiabetes, or non-insulin-dependent diabetes (NIDDM), often occursconcurrent with normal, or even elevated levels of insulin, and appearto be the result of the inability of tissues to respond appropriately toinsulin (i.e., insulin resistance). Insulin resistance is a majorsusceptibility trait of NIDDM and also is a contributing factor inarteriosclerosis, hypertension, lipid disorders and polycystic ovariansyndrome.

Conventional treatments for NIDDM have not changed substantially in manyyears and have significant limitations. While physical exercise and areduction in dietary intake of calories can improve the diabeticcondition, compliance with this treatment is generally poor. To increasethe plasma level of insulin, physicians sometimes administersulfonylureas (e.g., tolbutamide, glipizide). The sulfonylureasstimulate the pancreatic beta-cells to secrete more insulin. The plasmalevel of insulin can be directly increased by injecting insulin afterthe response to sulfonylureas fails and will result in insulinconcentrations that stimulate even highly insulin-resistant tissues.However, dangerously low levels of plasma glucose can result from theselast two treatments, and can theoretically lead to increased insulinresistance due to the even higher plasma insulin levels.

Biguanides have been the most widely used class of antidiabetics. Theyact by increasing insulin activity in peripheral tissues, reducinghepatic glucose output due to inhibition of gluconeogenesis, andreducing the absorption of glucose from the intestine. Metformin,phenformin, buformin, etc. belong to this group. Metformin has beenwidely prescribed for lowering blood glucose in patients with NIDDM andis marketed in 500, 750, 850 and 1000 mg strengths. However, because itis a short acting drug, metformin requires twice-daily orthree-times-daily dosing (500-850 mg tab 2-3/day or 1000 mg bid withmeals). Adverse events associated with metformin include anorexia,nausea, vomiting and diarrhea. The adverse events may be partiallyavoided by either reducing the initial dose and/or the maintenance doseby taking an extended-release dosage form rather than a multiple dailydoses. Besides reducing the adverse events, administering anextended-release dosage form provides a reduction in the frequency ofadministration.

More recently, glitazones have been introduced and are widely used inthe treatment of NIDDM. These agents substantially increase insulinsensitivity in muscle, liver, and adipose tissue in several NIDDM animalmodels, resulting in the correction of elevated plasma levels ofglucose, triglycerides and nonesterified fatty acids without theoccurrence of hypoglycemia. These agents, also known generically asthiazolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone),function by increasing the sensitivity of peripheral tissues, such asskeletal muscle, towards insulin. Pioglitazone, the most widely usedglitazone, is normally administered at doses from about 15 mg to about45 mg, and is given as a single dose once per day. Another glitazone,rosiglitazone, is administered at doses of about 5 mg to about 10 mg perday.

Biguanides and thiazolidinediones are commercially available in the formof tablets of the individual drugs. The tablets may be in the form ofeither immediate release (IR) formulations or controlled release (CR)formulations and are administered orally to patients in need thereof inprotocols calling for the single administration of the individualingredient. Metformin monotherapy is used as a first line treatment indiabetic patients but may be supplemented with other drugs when thesecondary failure of the therapy sets in. The addition of athiazolidinedione agent to concurrent biguanide treatment provides abalance of stimulated release of insulin while ameliorating insulinresistance and thus provides a level of glycemic control unattainable byeither medication alone.

Insulin resistance is a common feature characterizing the pathogenesisof Type II diabetes. Metformin improves glucose tolerance but cannotenhance insulin sensitivity. In contrast, glitazones improve glycemiccontrol by improving insulin sensitivity. The glitazones are highlyselective and potent agonists for the peroxisome proliferator-activatedreceptor-gamma (PPAR-γ). Activation of PPAR-γ nuclear receptorsregulates the transcription of insulin responsive genes involved in thecontrol of glucose production, transport, and utilization. In addition,PPAR-γ-responsive genes also participate in the regulation of fatty acidmetabolism. The antidiabetic activity of glitazones has beendemonstrated in those Type II diabetes in which hyperglycemia and/orimpaired glucose tolerance is a consequence of insulin resistance intarget tissues. A single administration of glitazones activates theinsulin receptors for an extended period and may thus be administered asa single dose without there being a need to maintain the plasmaconcentration.

A combination therapy of a biguanide and a glitazone, therefore, has asynergistic effect on glucose control because both agents act bydifferent but complementary mechanisms. Clinical evaluations havedemonstrated the method of treating diabetes by employing combinationsof biguanides and glitazones (WO 00/27401 and U.S. Pat. No. 6,011,049).Moreover, pharmaceutical compositions having combinations of biguanidesand thiazolidinediones and providing controlled or immediate release ofboth of the drugs are known in the art. For example, U.S. Pat. No.6,296,874 and published U.S. patent application Ser. Nos. 20010036478A1, 2010034374 A1, and 20010046545 A1 (Adjei et al.) describe controlledrelease core combinations of a glitazone with a biguanide chosen frommetformin, phenformin or buformin in a single dosage form. The patentapplications of Adjei et al. disclose the preparation of suchcombinations using either silicate polymers or polysaccharides.

U.S. Pat. Nos. 6,166,043 and 6,172,090 disclose methods for reducing theamounts and side effects of active components administered to a diabeticpatient. One method disclosed includes administering a therapeuticallyeffective amount of an insulin sensitivity enhancer in combination witha biguanide. The insulin sensitivity enhancer in the system is athiazolidinedione selected from pioglitazone and troglitazone, while thebiguanide is selected from metformin, phenformin and buformin. Thecombination may be administered as an admixture of the agents or theagents administered independently. The thiazolidinedione and thebiguanide may be in the form of a conventional immediate releasecomposition.

Although combinations of two antidiabetic agents are known in the artand are convenient to formulate, a combination providing extendedrelease of a water-soluble active ingredient, e.g., a biguanide, andimmediate release of a water-insoluble or sparingly soluble active,e.g., a glitazone, is difficult to achieve.

SUMMARY OF THE INVENTION

In one general aspect there is provided a solid pharmaceutical dosageform for oral administration. The dosage form includes an extendedrelease layer that includes a biguanide and an immediate release layerthat includes a glitazone.

Embodiments of the dosage form may include one or more of the followingfeatures. For example, the biguanide may be one or more of metformin,phenformin, and buformin. The glitazone may be one or more ofpioglitazone, rosiglitazone, troglitazone, ciglitazone and englitazone.After oral administration the biguanide may be released over a period ofabout 4 to about 36 hours and, more particularly, over a period of about8 to about 24 hours.

The dosage form may be tablets or capsules. The tablet may include acoating. The capsules may include one or more of pellets, beads,granules, multiparticulates, tablets and powder.

The extended release layer may be a matrix and the matrix may have auniform mixture of the biguanide and one or more rate controllingpolymers. The one or more rate-controlling polymers may be hydrophilicpolymers, hydrophobic polymers, or a combination thereof. The matrix mayfurther include one or more pharmaceutically acceptable excipients. Thepharmaceutically acceptable excipients may be one or more of diluents,lubricants, disintegrants, binders, glidants, coloring and flavoringagents.

The biguanide may layered onto a pharmaceutically inert core or seed.The inert core or seed may be hydrosoluble or hydroinsoluble.

The immediate release outer layer may further include film-formingpolymers and optionally other pharmaceutically acceptable excipients.The film-forming polymers may be water-soluble polymers. Thepharmaceutically acceptable excipients may be one or more ofplasticizers, opacifiers and colorants.

The dosage form may further include a wetting agent in the immediaterelease layer such that the immediate release layer includes a glitazoneand the wetting agent in a weight ratio ranging from about 10:1 to about1:25. The wetting agent may be selected from amongst hydrophilic andhydrophobic surfactants. The hydrophilic surfactants may be selectedfrom one or more of non-ionic surfactants, ionic surfactants or mixturesthereof.

The hydrophobic surfactants may be selected from one or more ofalcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty acidmonoesters; glycerol fatty acid diesters; acetylated glycerol fatty acidmonoesters; acetylated glycerol fatty acid diesters, lower alcohol fattyacid esters; polyethylene glycol fatty acid esters; polyethylene glycolglycerol fatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives of monoglycerides;lactic acid derivatives of diglycerides; propylene glycol diglycerides;sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers, polyethyleneglycolsas esters or ethers, polyethoxylated castor oil; polyethoxylatedhydrogenated castor oil, polyethoxylated fatty acid from castor oil orpolyethoxylated fatty acid from castor oil or polyethoxylated fatty acidfrom hydrogenated castor oil.

The non-ionic surfactants may be selected from one or more ofalkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; caprylocaproyl macrogolglycerides, polyoxyethylenealkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fattyacid esters; polyethylene glycol glycerol fatty acid esters;polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fattyacid esters; polyoxyethylene glycerides; polyoxyethylene sterols,derivatives, and analogues thereof; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction products ofpolyols and at least one member of the group consisting of fatty acids,glycerides, vegetable oils, hydrogenated vegetable oils, and sterols;sugar esters, sugar ethers; sucroglycerides; and mixtures thereof.

The ionic surfactants may be selected from one or more of alkyl ammoniumsalts; bile acids and salts, analogues, and derivatives thereof; fattyacid derivatives of amino acids, oligopeptides, and polypeptides;glyceride derivatives of amino acids, oligopeptides, and polypeptides;acyl lactylates; monoacetylated tartaric acid esters of monoglycerides,monoacetylated tartaric acid esters of diglycerides, diacetylatedtartaric acid esters of monoglycerides, diacetylated tartaric acidesters of diglycerides; succinylated monoglycerides; citric acid estersof monoglycerides; citric acid esters of diglycerides; alginate salts;propylene glycol alginate; lecithins and hydrogenated lecithins;lysolecithin and hydrogenated lysolecithins; lysophospholipids andderivatives thereof; phospholipids and derivatives thereof; salts ofalkylsulfates; salts of fatty acids; sodium docusate; and mixturesthereof.

The extended release layer may be a core and the immediate release layermay cover at least a portion of the core. The dosage form may be abilayered dosage form. The dosage form may further include one or moreof sulfonylurea, insulin, alpha-glucosidase inhibitors, meglitinides,fibrates, statins, squalene synthesis inhibitors andangiotensin-converting enzyme inhibitors.

In another general aspect there is provided a process for preparing asolid, orally administered pharmaceutical dosage form of an extendedrelease core of a biguanide and an immediate release layer of aglitazone. The process includes (a.) dispersing the biguanide in a solidmatrix to form a core having a surface; and (b.) layering the immediaterelease layer of a glitazone on the surface of the core.

Embodiments of the process may include one or more of the followingfeatures. For example, layering the immediate release layer may furtherinclude layering one or more wetting agents. The glitazone and the oneor more wetting agents may be present in the immediate release layer ina weight ratio ranging from about 10:1 to about 1:25. The one or morewetting agents may be selected from amongst hydrophilic or hydrophobicsurfactants. The hydrophilic surfactants may be selected from one ormore of non-ionic surfactants, ionic surfactants or mixtures thereof.

The hydrophobic surfactants may be selected from one or more ofalcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty acidmonoesters; glycerol fatty acid diesters; acetylated glycerol fatty acidmonoesters; acetylated glycerol fatty acid diesters, lower alcohol fattyacid esters; polyethylene glycol fatty acid esters; polyethylene glycolglycerol fatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives of monoglycerides;lactic acid derivatives of diglycerides; propylene glycol diglycerides;sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers, polyethyleneglycolsas esters or ethers, polyethoxylated castor oil; polyethoxylatedhydrogenated castor oil, polyethoxylated fatty acid from castor oil orpolyethoxylated fatty acid from castor oil or polyethoxylated fatty acidfrom hydrogenated castor oil.

The non-ionic surfactants may be selected from one or more ofalkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; caprylocaproyl macrogolglycerides, polyoxyethylenealkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fattyacid esters; polyethylene glycol glycerol fatty acid esters;polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fattyacid esters; polyoxyethylene glycerides; polyoxyethylene sterols,derivatives, and analogues thereof; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction products ofpolyols and at least one member of the group consisting of fatty acids,glycerides, vegetable oils, hydrogenated vegetable oils, and sterols;sugar esters, sugar ethers; sucroglycerides; and mixtures thereof.

The ionic surfactants may be selected from amongst alkyl ammonium salts;bile acids and salts, analogues, and derivatives thereof; fatty acidderivatives of amino acids, oligopeptides, and polypeptides; glyceridederivatives of amino acids, oligopeptides, and polypeptides; acyllactylates; monoacetylated tartaric acid esters of monoglycerides,monoacetylated tartaric acid esters of diglycerides, diacetylatedtartaric acid esters of monoglycerides, diacetylated tartaric acidesters of diglycerides; succinylated monoglycerides; citric acid estersof monoglycerides; citric acid esters of diglycerides; alginate salts;propylene glycol alginate; lecithins and hydrogenated lecithins;lysolecithin and hydrogenated lysolecithins; lysophospholipids andderivatives thereof; phospholipids and derivatives thereof; salts ofalkylsulfates; salts of fatty acids; sodium docusate; and mixturesthereof

The biguanide may be selected from one or more of metformin, phenforminand buformin. The glitazone may be selected from one or more ofpioglitazone, rosiglitazone, troglitazone, ciglitazone and englitazone.After oral administration the biguanide may be released over a period ofabout 4 to about 36 hours and, more particularly, over a period of about8 to about 24 hours.

The process may further include forming a tablet or a capsule. Theprocess may still further include coating the tablet. The capsule maycontain one or more of pellets, beads, granules, multiparticulates,tablets and powder.

The core may be a matrix and the matrix may be a uniform mixture of thebiguanide and one or more rate controlling polymers. The one or morerate-controlling polymers may be either or both of hydrophilic andhydrophobic. The matrix may further include one or more pharmaceuticallyacceptable excipients. The pharmaceutically acceptable excipients mayinclude one or more of diluents, lubricants, disintegrants, binders,glidants, colorants, and flavorants.

The biguanide may be layered onto pharmaceutically inert core or seeds.The inert core or seeds may be hydrosoluble or hydroinsoluble.

The immediate release outer layer may further include film-formingpolymers and optionally other pharmaceutically acceptable excipients.The film-forming polymers may be water-soluble polymers. Thepharmaceutically acceptable excipients may be one or more ofplasticizers, opacifiers and colorants.

The process may further include placing a seal-coat over the core, theseal-coat including hydrophilic polymers.

In another general aspect there is provided a process for preparing abilayered, solid, orally administered pharmaceutical dosage form of abiguanide and a glitazone. The process includes (a.) dispersing thebiguanide in an extended release carrier base material; (b.) separatelydispersing the glitazone in an immediate release carrier base material;and (c.) compressing the material of step a and step b to form bilayeredtablet.

Embodiments of the process may include one or more of the followingfeatures. For example, the immediate release carrier base material mayfurther include one or more wetting agents before or after dispersingthe glitazone. The glitazone and the one or more wetting agents may bepresent in a weight ratio ranging from about 10:1 to about 1:25. The oneor more wetting agents may be selected from amongst hydrophilic orhydrophobic surfactants. The hydrophilic surfactants may be selectedfrom one or more of non-ionic surfactants, ionic surfactants or mixturesthereof.

The hydrophobic surfactants may be selected from one or more ofalcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty acidmonoesters; glycerol fatty acid diesters; acetylated glycerol fatty acidmonoesters; acetylated glycerol fatty acid diesters, lower alcohol fattyacid esters; polyethylene glycol fatty acid esters; polyethylene glycolglycerol fatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives of monoglycerides;lactic acid derivatives of diglycerides; propylene glycol diglycerides;sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers, polyethyleneglycolsas esters or ethers, polyethoxylated castor oil; polyethoxylatedhydrogenated castor oil, polyethoxylated fatty acid from castor oil orpolyethoxylated fatty acid from castor oil or polyethoxylated fatty acidfrom hydrogenated castor oil.

The non-ionic surfactants may be selected from one or more ofalkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; caprylocaproyl macrogolglycerides, polyoxyethylenealkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fattyacid esters; polyethylene glycol glycerol fatty acid esters;polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fattyacid esters; polyoxyethylene glycerides; polyoxyethylene sterols,derivatives, and analogues thereof; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction products ofpolyols and at least one member of the group consisting of fatty acids,glycerides, vegetable oils, hydrogenated vegetable oils, and sterols;sugar esters, sugar ethers; sucroglycerides; and mixtures thereof.

The ionic surfactants may be selected from amongst alkyl ammonium salts;bile acids and salts, analogues, and derivatives thereof; fatty acidderivatives of amino acids, oligopeptides, and polypeptides; glyceridederivatives of amino acids, oligopeptides, and polypeptides; acyllactylates; monoacetylated tartaric acid esters of monoglycerides,monoacetylated tartaric acid esters of diglycerides, diacetylatedtartaric acid esters of mono glycerides, diacetylated tartaric acidesters of diglycerides; succinylated monoglycerides; citric acid estersof monoglycerides; citric acid esters of diglycerides; alginate salts;propylene glycol alginate; lecithins and hydrogenated lecithins;lysolecithin and hydrogenated lysolecithins; lysophospholipids andderivatives thereof; phospholipids and derivatives thereof; salts ofalkylsulfates; salts of fatty acids; sodium docusate; and mixturesthereof.

The biguanide may be selected from one or more of metformin, phenforminand buformin. The glitazone may be selected from one or more ofpioglitazone, rosiglitazone, troglitazone, ciglitazone and englitazone.

After oral administration, the biguanide is released over a period ofabout 4 to about 36 hours and, more particularly, over a period of about8 to about 24 hours.

The process may further include forming a tablet or a capsule. Theprocess may still further include coating the tablet. The capsule maycontain one or more of pellets, beads, granules, multiparticulates,tablets and powder.

The biguanide layer may be a matrix and the matrix may be a uniformmixture of the biguanide and one or more rate controlling polymers. Theone or more rate-controlling polymers may be either or both ofhydrophilic polymers and hydrophobic polymers. The matrix may furtherinclude one or more pharmaceutically acceptable excipients. Thepharmaceutically acceptable excipients may be one or more of diluents,lubricants, disintegrants, binders, glidants, colorants, and flavorants.The biguanide may be layered onto pharmaceutically inert core or seeds.The inert core or seeds may be hydrosoluble or hydroinsoluble.

The immediate release carrier base material may further include one ormore film-forming polymers and optionally other pharmaceuticallyacceptable excipients. The film-forming polymers may be water-solublepolymers. The pharmaceutically acceptable excipients may be one or moreof plasticizers, opacifiers and colorants.

The process may further include providing a seal-coat of one or morehydrophilic polymers between the two layers.

In another general aspect there is provided a method of treatingnon-insulin dependent diabetes mellitus in a patient in need thereof.The method includes administering a solid, pharmaceutical dosage form ofthe combination of a biguanide and a glitazone. The dosage form providesan extended-release of the biguanide and an immediate release of theglitazone.

Embodiments of the method may include one or more of the followingfeatures or those described above. For example, the biguanide may be oneor more of metformin, phenformin, and buformin and, in particular, maybe metformin. The glitazone may be one or more of pioglitazone,rosiglitazone, troglitazone, ciglitazone and englitazone and, inparticular, may be pioglitazone.

After oral administration of the dosage form, the biguanide is releasedover a period of about 4 to about 36 hours and, more particularly, overa period of about 8 to about 24 hours. The dosage form may be tablets orcapsules. The dosage form may further include one or more ofsulfonylurea, insulin, alpha-glucosidase inhibitors, meglitinides,fibrates, statins, squalene synthesis inhibitors andangiotensin-converting enzyme inhibitors.

The details of one or more embodiments of the inventions are set forthin the description below. Other features, objects and advantages of theinventions will be apparent from the description and claims.

DETAILED DESCRIPTION OF THE INVENTION

Hydrophobic therapeutic agents, i.e., therapeutic compounds having poorsolubility in aqueous solution, are difficult to formulate as a dosageform that can be effectively administered to patients. A well-designedformulation must, at a minimum, be capable of presenting atherapeutically effective amount of the hydrophobic compound to thedesired absorption site, in an absorbable form. Even this minimalfunctionality is difficult to achieve when delivery of the hydrophobictherapeutic agent requires interaction with aqueous physiologicalenvironments, such as gastric and intestinal fluids. Pharmaceuticalcompositions for delivering such hydrophobic therapeutic agents mustcarry the hydrophobic compound through the aqueous environment whileboth maintaining the hydrophobic compound in an absorbable form andavoiding the use of physiologically harmful solvents or excipients.

A similar problem is faced when formulating extended release dosageforms of highly soluble therapeutic agents. The high solubility of thetherapeutic agent requires the incorporation of a high percentage of thepolymer to achieve a desired release profile and prolonged effect.Further, an additional constraint is the necessity of controlling theinitial burst of the drug from the formulation.

Therefore, there remains a need for pharmaceutical compositions for oraladministration that include a combination of one or more hydrophobic,water-insoluble therapeutic agents, i.e., a glitazone, in immediaterelease form, and a highly water-soluble therapeutic agent, i.e., abiguanide, in an extended-release form with the characteristics ofachieving an effect over 24 hours after once daily administration.

It has now been discovered that a dosage form can be prepared thatincludes: (a) one layer or a core from which a single highlywater-soluble active ingredient is released on a prolonged basis and (b)a coating or layer from which another active ingredient is released onan immediate-release basis. The dosage form provides a high degree ofuniformity in the immediate-release portion, even in those circumstancesin which the drug in the immediate-release portion is either insolubleor only sparingly soluble in water. This result is achieved byincorporating one or more wetting agents in the immediate release layerin an amount in which the weight ratio of the glitazone to wetting agentranges from 10:1 to about 1:25.

Specifically, in one aspect there is provided a dosage form thatcontains both a glitazone and a biguanide. The glitazone is contained inan immediate-release form so that it is released substantiallyimmediately upon ingestion (i.e., upon swallowing). Generally at least80% of the glitazone is released from the dosage form within an hourafter administration. The biguanide, by contrast, releases in asustained fashion; at least about 75% of the drug contained in thedosage form is released over a period of 4 to 36 hours, preferably about8 to 24 hours. The term “about” as used above and elsewhere herein meansplus or minus 10% for each of the numerical limits.

The pharmaceutical compositions of the present invention can beadministered orally in the form of tablets, such as coated-tablets,bilayered tablets or multi-layered tablets, or in form of capsulescontaining pellets, beads, granules, multiparticulates, tablets orpowder.

Biguanide as employed herein is intended to include metformin,phenformin and buformin including their salts, solvates, hydrates andpolymorphs. Particularly, the biguanide used may be metformin. Differentsalts of metformin that can be used include hydrochloride, acetate,maleate, fumarate, succinate and other salts. The daily effective doseof metformin may range from about 500 mg to about 2550 mg, and, inparticular, the dose may be a single dose of about 500 mg to about 1000mg. The biguanide is present in an amount from about 40% to about 75% byweight of the total composition.

The biguanide may be incorporated in an extended release carrier base bydispersing the biguanide in a rate-controlling polymer matrix, asdescribed in our pending application, published as WO 03/028704.Alternatively, the biguanide may be layered onto pharmaceuticallyacceptable inert cores or seeds in admixture with rate-controllingpolymers or surrounded by rate-controlling polymers.

The term matrix, as used herein, refers to a uniform mixture of abiguanide, rate-controlling polymers, and, optionally, otherpharmaceutically acceptable excipients. The rate-controlling polymersmay be hydrophilic, hydrophobic or a combination thereof. Therate-controlling polymers are uniformly dispersed throughout the matrixto achieve uniform drug release. Hydrophilic polymers of the presentinvention include, for example, cellulose derivatives such ashydroxypropylcellulose, hydroxypropyl methylcellulose,hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose,methylcellulose, sodium carboxymethylcellulose or combinations thereof.The hydrophobic polymers include one or more of poly(ethylene)oxide,ethyl cellulose, cellulose acetate, cellulose acetate butyrate,hydroxypropyl methylcellulose phthalate, poly(alkyl)methacrylate,copolymers of acrylic or methacrylic acid esters, waxes, shellac, andhydrogenated vegetable oils.

In addition to the one or more active ingredients and rate-controllingpolymers, the matrix may contain other pharmaceutically acceptableexcipients that act in one or more capacities as diluents, binders,lubricants, glidants, colorants or flavoring agents.

Suitable diluents include pharmaceutically acceptable inert fillers suchas microcrystalline cellulose, lactose, dibasic calcium phosphate,mannitol, starch, sorbitol, sucrose, dextrose, maltodextrin or mixturesthereof

Suitable binders include one or more of polyvinyl pyrrolidone, lactose,starches, gums, waxes, gelatin, polymers or mixtures thereof.

Suitable lubricants include one or more of colloidal silicon dioxide,talc, stearic acid, magnesium stearate, magnesium silicate,polyethylene, sodium benzoate, sodium lauryl sulphate, fumaric acid,zinc stearate, paraffin, or mixtures thereof.

Suitable glidants include one or more of talc and colloidal silicondioxide.

The matrix may be made by any pharmaceutically acceptable technique thatachieves uniform blending, e.g., dry blending, dry granulation, wetgranulation, compaction, and fluid bed granulation.

The matrix formed can be compressed to form the tablets. Alternatively,the matrix may be formulated as a plurality of discrete or aggregatedparticles, pellets, beads or granules.

As described above, the biguanide may be layered onto cores or seeds.The inert core or seeds may be hydro soluble, such as sucrose, lactose,maltodextrin and the like, or hydro insoluble, such as microcrystallinecellulose, partially pregelatinized starch, dicalcium phosphate and thelike. The biguanide and the rate controlling polymer can be coated assingle layer or as separate layers on these inert cores, granulated withthe inert cores, or mixed with the inert cores and extruded andspheronized to form the pellets.

The coating may be applied to the inert/active core using a conventionalcoating pan, a spray coater, a rotating perforated pan, or an automatedsystem, such as a centrifugal fluidizing (CF) granulator, a fluidizedbed process, or any other suitably automated coating equipment.

The extended-release core containing a biguanide may optionally becoated to seal the core. The coated active cores may be dried underconditions effective for drying, e.g., in an oven or by means of gas ina fluidized bed.

Finally, these beads/pellets may be filled into capsules or compressedto form the tablets. The capsule dosage form may include a plurality ofpellets, granules or beads or a single compressed tablet which releasethe biguanide over an extended period of time.

Glitazone as employed herein is intended to include, but is not limitedto, pioglitazone, rosiglitazone, troglitazone, ciglitazone, englitazone,and their salts, solvates, hydrates and polymorphs. In particular, theglitazone may be pioglitazone. The daily effective dose of pioglitazonemay range from 5 mg to 50 mg and, in particular, the dose may be asingle dose of 10 mg to 45 mg. The glitazone may be present in an amountof from about 0.5% to about 10% by weight of the total composition.

A glitazone can be incorporated into the dosage form as an immediaterelease component in a variety of ways. For example, it can beincorporated into an exterior coating of a tablet from which it releasessubstantially immediately upon ingestion. Such a coating can similarlybe applied to each of the particles that make up a multiparticulatesystem, i.e., granules, beads. If the dosage form is to be a capsule,the glitazone can be contained in a single pellet inside the capsulefrom which it releases substantially immediately once the capsule shelldissolves. Alternatively, the glitazone can be contained in severalsmaller pellets, can be present as one or more immediate releaseparticles, or can be present as one or more immediate release layersover the extended release cores or beads. Any conventional method may beused for the preparation of the layer of the glitazone. Conventionalpharmaceutically acceptable excipients may be incorporated into thislayer. These excipients may include diluents, binders and lubricants.

The coating composition for coating the glitazone may includewater-soluble polymers such as polyvinyl pyrrolidine, hydroxypropylcellulose, polyvinyl alcohol, hydroxypropyl methylcellulose and thelike. The polymer may be applied as a solution in an organic solvent oras an aqueous dispersion. The solvent may be, for example, one or moreof water; alcohol such as ethyl alcohol or isopropyl alcohol; ketonessuch as acetone or ethylmethyl ketone; and chlorinated hydrocarbons suchas dichloroethane and trichloroethane. The coating composition may alsoinclude plasticizers, opacifiers and colorants. Any conventional coatingequipment may be employed to facilitate coating, including a centrifugalfluidized bed coating apparatus, pan coating apparatus, or fluidized bedgranulating coating apparatus.

Due to poor dispersibility in solvents, the film-coating compositionthat includes the glitazone may optionally include a wetting agent.Suitable wetting agents include hydrophilic and hydrophobic surfactants.Hydrophilic surfactants may be selected from one or more of hydrophilicnon-ionic surfactants, hydrophilic ionic surfactants, and combinationsthereof.

Non-ionic surfactants may be selected from one or more ofalkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; caprylocaproyl macrogolglycerides, polyoxyethylenealkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fattyacid esters; polyethylene glycol glycerol fatty acid esters;polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fattyacid esters; polyoxyethylene glycerides; polyoxyethylene sterols,derivatives, and analogues thereof; polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction products ofpolyols and at least one member of the group consisting of fatty acids,glycerides, vegetable oils, hydrogenated vegetable oils, and sterols;sugar esters, sugar ethers; sucroglycerides; and mixtures thereof.

Ionic surfactants may be selected from one or more of alkyl ammoniumsalts; bile acids and salts, analogues, and derivatives thereof; fattyacid derivatives of amino acids, oligopeptides, and polypeptides;glyceride derivatives of amino acids, oligopeptides, and polypeptides;acyl lactylates; monoacetylated tartaric acid esters of monoglycerides,monoacetylated tartaric acid esters of diglycerides, diacetylatedtartaric acid esters of monoglycerides, diacetylated tartaric acidesters of diglycerides; succinylated monoglycerides; citric acid estersof monoglycerides; citric acid esters of diglycerides; lysolecithin andhydrogenated lysolecithins; lysophospholipids and derivatives thereof;phospholipids and derivatives thereof; salts of alkylsulfates; salts offatty acids; sodium docusate; and mixtures thereof.

Hydrophobic surfactants may be selected from one or more of alcohols;polyoxyethylene alkylethers; fatty acids; glycerol fatty acidmonoesters; glycerol fatty acid diesters; acetylated glycerol fatty acidmonoesters; acetylated glycerol fatty acid diesters, lower alcohol fattyacid esters; polyethylene glycol fatty acid esters; polyethylene glycolglycerol fatty acid esters; polypropylene glycol fatty acid esters;polyoxyethylene glycerides; lactic acid derivatives of monoglycerides;lactic acid derivatives of diglycerides; propylene glycol diglycerides;sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers, polyethyleneglycolsas esters or ethers, polyethoxylated castor oil; polyethoxylatedhydrogenated castor oil, polyethoxylated fatty acid from castor oil orpolyethoxylated fatty acid from castor oil or polyethoxylated fatty acidfrom hydrogenated castor oil.

The glitazone and the wetting agent may be present in a weight ratioranging from about 10:1 to about 1:25.

Of one of the embodiments, there is provided a bilayered dosage form forthe combination of a biguanide and a glitazone. The term ‘bilayered’ asused herein is meant to encompass solid dosage forms in which there aretwo separate drug layers, with only one surface in contact with eachother. These may be prepared, for example, by compressing additionalgranulation on a previously compressed granulation or alternatively byfeeding previously compressed tablets into a machine and compressinganother granulation layer around the preformed tablets.

An example of a bi-layer tablet manufacturing method includes: (1)blending a quantity of a glitazone with various excipients, colorants,and/or other pharmaceutically acceptable excipients and additives toform an immediate release formulation, (2) blending a quantity of abiguanide with a rate-controlling polymer, and various excipients,colorants, and/or other pharmaceutical additives to form an extendedrelease formulation, and (3) compressing a quantity of the immediaterelease formulation of the glitazone with a quantity of the extendedrelease formulation of the biguanide to form a bi-layer tablet.

One of the embodiments includes providing a seal coat of hydrophilicpolymers between the extended-release and immediate-release layers.

Other embodiments include modifications relating to coating the tabletwith the polymer in order to modify the release of the drug. The soliddosage forms may be optionally coated with non-functional coatings wellknown in the art, or with coatings that further modify the release ofthe drug from the dosage form. All such modifications as may be done andunderstood by those who are skilled in the art are within the scope ofthe present invention. For example, one such modification includesmaking the composition into a layered tablet in which the compositionprovides extended release of more than one therapeutic agent, orextended release of one of the therapeutic agents and immediate ordelayed release of the other therapeutic agent(s).

EXAMPLE 1

INGREDIENTS Mg/tablet CORE Metformin Hydrochloride 500 MicrocrystallineCellulose 245 Sodium Carboxymethyl Cellulose 150 Purified Water q.s.Hydroxypropyl methylcellulose 100 Magnesium Stearate 5 SEALHydroxypropyl methylcellulose E5 15.6 COAT Polyethylene glycol 4000 4.8Titanium Dioxide 2.4 Talc 1.2 Purified Water q.s. ACTIVE PioglitazoneHydrochloride equivalent 39.672 COAT to Pioglitazone (30 mg)Caprylocaporyl Macrogolglycerides 18 Hydroxypropyl methylcellulose E540.3 Polyethylene glycol 4000 12.4 Titanium Dioxide 6.2 Talc 3.1Purified Water q.s.Procedure:

1. Metformin hydrochloride was milled through a 1 mm screen and mixedwith microcrystalline cellulose and sodium carboxymethyl cellulose. Theblend was sieved through a No. 44 mesh, transferred to a rapid mixergranulator, and wet granulated with purified water. The granules weredried in a fluid bed dryer, sized through a multimill, and siftedthrough a No. 30 mesh.

2. Hydroxypropyl methylcellulose was separately sifted through a No. 30mesh and mixed with the granules of step 1 in a low shear mixer. Theblend was then mixed with magnesium stearate and compressed intotablets.

3. A coating dispersion was prepared by dispersing all of theingredients of the seal coat in water. The tablets were coated with thisdispersion until a weight build up of 2% was achieved.

4. To prepare the active coat, caprylocaproyl monoglyceride wasdissolved in purified water. To this solution, pioglitazonehydrochloride was added with stirring to form a dispersion. The otheringredients of the active coat were added with stirring to thisdispersion and the resulting dispersion was then spray coated upon thetablets obtained from step 3 until a weight build up of 10% wasachieved.

EXAMPLE 2

INGREDIENTS Mg/tablet CORE Metformin Hydrochloride 500 MicrocrystallineCellulose 245 Sodium Carboxymethyl Cellulose 150 Hydroxypropylmethylcellulose 100 Magnesium Stearate 5 SEAL Hydroxypropylmethylcellulose E5 15.6 COAT Polyethylene glycol 4000 4.8 TitaniumDioxide 2.4 Talc 1.2 Purified Water q.s. ACTIVE PioglitazoneHydrochloride equivalent 39.672 COAT to Pioglitazone (30 mg)Hydroxypropyl methylcellulose E5 37.2 Polyethylene glycol 400 7.2Titanium Dioxide 6.2 Talc 12.0 Methylene chloride q.s. Isopropyl alcoholq.s.Procedure:

1. Metformin hydrochloride was milled through a 1 mm screen and mixedwith microcrystalline cellulose and sodium carboxymethyl cellulose. Theblend was sieved through a No. 44 mesh.

2. Hydroxypropyl methylcellulose was separately sifted through a No. 30mesh and mixed with the blend of step 1 in a low shear mixer. The blendwas then mixed with magnesium stearate compressed into tablets.

3. A coating dispersion was prepared by dispersing all of theingredients of the seal coat in water. The tablets were coated with thisdispersion until a weight build up of 2% was achieved.

4. To prepare the active coat, pioglitazone hydrochloride was dissolvedin a methylene chloride and isopropyl alcohol mix (ratio of 2:1). Theother ingredients of the active coat then were added with stirring tothis solution and the resulting dispersion was spray coated upon thetablets obtained from step 3 until a weight build up of 10% wasachieved.

EXAMPLE 3

INGREDIENTS Mg/tablet CORE Metformin Hydrochloride 500 MicrocrystallineCellulose 245 Sodium Carboxymethyl Cellulose 150 Hydroxypropylmethylcellulose 100 Magnesium Stearate 5 SEAL Hydroxypropylmethylcellulose E5 15.6 COAT Polyethylene glycol 4000 4.8 TitaniumDioxide 2.4 Talc 1.2 Purified Water q.s. ACTIVE PioglitazoneHydrochloride equivalent 19.836 COAT to Pioglitazone (15 mg)Caprylocaporyl Macrogolglycerides 14.4 Hydroxypropyl methylcellulose E540.3 Polyethylene glycol 4000 12.4 Titanium Dioxide 6.2 Talc 3.1Purified Water q.s.Procedure:

1. Metformin hydrochloride was milled through a 1 mm screen and mixedwith microcrystalline cellulose and sodium carboxymethyl cellulose. Theblend was sieved through a No. 44 mesh.

2. Hydroxypropyl methylcellulose was separately sifted through a No. 30mesh and mixed with the blend of step 1 in a low shear mixer. The blendwas then mixed with magnesium stearate, passed through a rollercompactor, and milled again to form granules. These granules were thencompressed into tablets.

3. A coating dispersion was prepared by dispersing all of theingredients of the seal coat in water. The tablets were coated with thisdispersion until a weight build up of 2% was achieved.

4. To prepare the active coat, caprylocaproyl monoglyceride wasdissolved in purified water. To this solution, pioglitazonehydrochloride was added with stirring to form dispersion. The otheringredients of the active coat were added with stirring to thisdispersion and the resulting dispersion was spray coated upon thetablets obtained from step 3 until the weight build up of 8.0% wasachieved.

A comparative dissolution profile of metformin hydrochloride in theinnovator's marketed tablets (Glucophage XR 500 mg) and tabletformulation made in accordance with the invention disclosed in Example 3was obtained. The dissolution was carried out in USP Apparatus Type I(basket) at a speed of 100 rpm. The medium was 900 ml phosphate bufferpH 6.8. The data obtained is disclosed in Table 1. TABLE 1 Comparativedissolution profile of metformin hydrochloride in Glucophage XR 500 mgversus the tablets of Example 3 Percent (%) Time Metformin hydrochloridereleased (hrs) Glucophage XR Tablets (Example 3) 0 0 0 1 29 28 2 41 43 460 65 8 83 92 10 90 100 12 99 101

From the results, it is evident that approximately all the drug isreleased in twelve hours in both formulations thereby showingsubstantially similar dissolution profiles.

A comparative dissolution profile of pioglitazone hydrochloride in theinnovator's marketed tablets (Actos, 15 mg) and tablet formulation madein accordance with Example 3 was obtained. The dissolution was carriedout in USP Apparatus Type I at a speed of 100 rpm. The medium was 900 ml0.1 N hydrochloric acid. The data obtained is disclosed in Table 2.TABLE 2 Comparative dissolution profile of pioglitazone hydrochloride inActos 15 mg versus tablets of Example 3 Percent (%) Time Pioglitazonehydrochloride released (hrs) Actos 15 mg Tablets (Example 3) 0 0 0 15100 95 30 101 104 45 101 106

From the results, it is evident that more than 95% of the drug isreleased in 15 minutes in both formulations thereby showingsubstantially similar dissolution profiles.

Pharmacokinetics

The drug release was evaluated in vivo in a randomized, two treatment,two period, single dose, crossover bioavailability study. The study wasconducted in twelve healthy, adult, male, human subjects under fastingconditions. A single OD dose of pioglitazone hydrochloride and 500 mgmetformin hydrochloride was administered after an overnight fasting of10 hours with 240 ml of 20% glucose water. The OD dosage was compared topioglitazone tablets 15 mg (Actos manufactured by TakedaPharmaceuticals, USA) and metformin extended release 500 mg tablets(Glucophage XR tablets manufactured by Bristol-Myers Squibb, USA). Therewas a washout period of seven days. All subjects were on fast overnightfor a period of 10 hours before commencement of dosing. Drinking waterwas not allowed from one hour pre-dosing to 10 hour post dosing. Uniformand low fat meals were provided to all the subjects.

The plasma pioglitazone and metformin concentrations were measured byhigh performance liquid chromatographic (HPLC) method using anultraviolet (UV) detector. The results are provided below.

Pioglitazone: The OD formulation showed a Tmax of 2.9±0.1287 as comparedto a Tmax of 3.02±0.3608 for the reference formulation, indicating thatthe test and reference formulations have substantially the same meanvalues.

The OD formulation gave a serum concentration time profile similar tothe reference formulation. The peak serum concentration (Cmax) wascomparable to that for the reference formulation, indicating a similarrate of absorption of pioglitazone. The total bioavailability ofpioglitazone measured as area under the curve (AUC 0-∝) was alsocomparable to that of the reference tablets, indicating that the entiredrug was released from the formulation and absorbed during its transitthrough gastrointestinal tract. These results are presented in Table 3.TABLE 3 Piaglitazone Pharmacokinetic Data Parameters Reference Test Cmax(ng/ml) 743.588 ± 67.44  727.724 ± 118.21  Tmax (hr)  3.02 ± 0.3608 2.90 ± 0.1287 AUC (0-∝) ng/ml · hr) 5835.98 ± 1284.71 5554.94 ± 1232.29

Further, referring to Table 4, the extent of absorption for the testproduct was comparable to that for the reference product as indicated bythe ratio of test to reference (T/R ratio). The 90% confidence intervalswere found to be within the bioequivalence acceptance range of 80-120%for the untransformed data (as per Drug Controller General of India(DCGI) draft guidelines). The results are shown in Table 4. TABLE 4 90%Confidence Intervals for Pioglitazone Pharmacokinetic data Ratio (%) 90%Confidence Parameters (Test/Reference) Intervals Cmax (ng/ml) 97.7590.97-104.53 Aug (0-∝) (ng/ml · hr) 94.79 86.92-102.66

Metformin: The OD formulation showed a Tmax of 3.88±0.8013 as comparedto 3.58±0.8940 of reference formulation, indicating that test andreference formulations have nearly same mean values.

Referring to Table 5, the OD formulation made in accordance with Example3 gave a serum concentration time profile similar to the referenceformulation. The peak serum concentration (Cmax) was comparable to thatfor the reference formulation, indicating a similar rate of absorptionof metformin hydrochloride. The total bioavailability of metforminmeasured as the area under the curve (AUC 0-∝) was also comparable tothat of the reference tablets, indicating that the entire drug wasreleased from the formulation and absorbed during its transit throughgastrointestinal tract. TABLE 5 Metformin Pharmacokinetic DataParameters Reference Test Cmax (ng/ml)  633.227 ± 109.33 670.527 ±116.392 Tmax (hr)   3.02 ± 0.3608  3.58 ± 0.8940 AUC (0-∝) ng/ml · hr)4653.866 ± 1463.9 4380.234 ± 1110.44 

Further, referring to Table 6, the extent of absorption for the testproduct was comparable to that for the reference product as indicated bythe ratio of test to reference (T/R ratio). The 90% confidence intervalswere found to be within the bioequivalence acceptance range of 80-120%for the untransformed data (as per DCG1 draft guidelines). TABLE 6 90%Confidence Intervals for Metformin Pharmacokinetic data Ratio (%) 90%Confidence Parameters (Test/Reference) Intervals Cmax (ng/ml) 107.2496.23-118.25 Aug (0-∝) (ng/ml · hr) 96.43 84.07-108.79

While several particular forms of the invention have been illustratedand described, it will be apparent that various modifications andcombinations of the invention detailed in the text can be made withoutdeparting from the spirit and scope of the invention. For example, abilayered tablet comprising an extended-release biguanide in one layerand an immediate-release glitazone in another layer may be prepared ofthe example given below.

EXAMPLE 4

Preparation of bilayered tablets: INGREDIENTS Mg/tablet MetforminMetformin Hydrochloride 500 layer Microcrystalline Cellulose 245 SodiumCarboxymethyl Cellulose 150 Hydroxypropyl methylcellulose 100 MagnesiumStearate 5 Seal Coat Hydroxypropyl methylcellulose E5 15.6 Polyethyleneglycol 4000 4.8 Titanium Dioxide 2.4 Talc 1.2 Pioglitazone Pioglitazonehydrochloride equiv. 39.672 layer to pioglitazone (30 mg) Lactose 80Hydroxypropyl cellulose 2.4 Carboxymethyl cellulose calcium 3.6Magnesium stearate 1.2 Purified water q.s.Procedure:

1. Metformin hydrochloride was milled and mixed with microcrystallinecellulose and sodium carboxymethyl cellulose. The blend was sieved.

2. Hydroxypropyl methylcellulose was separately sifted and mixed withthe blend of step 1 in a low shear mixer. The blend was then mixed withmagnesium stearate and passed through roller compactor and then milledagain to form granules.

3. Pioglitazone, lactose, hydroxypropyl cellulose andcarboxymethylcellulose calcium were blended and granulated with purifiedwater.

4. The wet mass of step 3 was granulated, dried and sifted.

5. The lubricated granules of metformin and pioglitazone were compressedinto bilayer tablets using a rotary compression machine.

Further, it is contemplated that any single feature or any combinationof optional features of the inventive variations described herein may bespecifically excluded from the claimed invention and be so described asa negative limitation. Accordingly, it is not intended that theinvention be limited, except as by the appended claims.

1. A solid pharmaceutical dosage form for oral administration, thedosage form comprising: an extended release layer comprising abiguanide; and an immediate release layer comprising a glitazone.
 2. Thedosage form of claim 1, wherein the biguanide comprises one or more ofmetformin, phenformin, and buformin.
 3. The dosage form of claim 1,wherein the biguanide is metformin.
 4. The dosage form of claim 1,wherein the glitazone comprises one or more of pioglitazone,rosiglitazone, troglitazone, ciglitazone and englitazone.
 5. The dosageform of claim 4, wherein the glitazone is pioglitazone.
 6. The dosageform of claim 1, wherein after oral administration the biguanide isreleased over a period of about 4 to about 36 hours.
 7. The dosage formof claim 6, wherein the biguanide is released over a period of about 8to about 24 hours.
 8. (canceled)
 9. (canceled)
 10. (canceled)
 11. Thedosage form of claim 1, wherein the extended release layer comprises amatrix.
 12. The dosage form of claim 11, wherein the matrix comprises auniform mixture of the biguanide and one or more rate controllingpolymers.
 13. (canceled)
 14. (canceled)
 15. (canceled)
 16. The dosageform of claim 1, wherein the biguanide is layered onto apharmaceutically inert core or seed.
 17. The dosage form of claim 16,wherein the inert core or seed is hydrosoluble or hydroinsoluble. 18.The dosage form of claim 1, wherein the immediate release outer layerfurther comprises film-forming polymers and optionally otherpharmaceutically acceptable excipients.
 19. (canceled)
 20. The dosageform of claim 18, wherein the pharmaceutically acceptable excipientscomprises one or more of plasticizers, opacifiers and colorants.
 21. Thedosage form of claim 1, further comprising one or more of sulfonylurea,insulin, alpha-glucosidase inhibitors, meglitinides, fibrates, statins,squalene synthesis inhibitors and angiotensin-converting enzymeinhibitors.
 22. The dosage form of claim 1, further comprising a wettingagent in the immediate release layer, wherein the immediate releaselayer comprises the glitazone and the wetting agent in a weight ratioranging from about 10:1 to about 1:25.
 23. (canceled)
 24. (canceled) 25.(canceled)
 26. (canceled)
 27. (canceled)
 28. The dosage form of claim 1,wherein the extended release layer comprises a core and the immediaterelease layer covers at least a portion of the core.
 29. The dosage formof claim 1, wherein the dosage form comprises a bilayered dosage form.30. A process for preparing a solid, orally administered pharmaceuticaldosage form of an extended release core of a biguanide and an immediaterelease layer of a glitazone, the process comprising: a. dispersing thebiguanide in a solid matrix to form a core having a surface; and b.layering the immediate release layer of the glitazone on the surface ofthe core.
 31. The process of claim 30, wherein layering the immediaterelease layer further comprises layering one or more wetting agents. 32.The process of claim 31, wherein the glitazone and the one or morewetting agents are present in the immediate release layer in a weightratio ranging from about 10:1 to about 1:25.
 33. (canceled) 34.(canceled)
 35. (canceled)
 36. (canceled)
 37. (canceled)
 38. (canceled)39. (canceled)
 40. (canceled)
 41. (canceled)
 42. (canceled) 43.(canceled)
 44. (canceled)
 45. (canceled)
 46. (canceled)
 47. (canceled)48. (canceled)
 49. (canceled)
 50. (canceled)
 51. (canceled) 52.(canceled)
 53. (canceled)
 54. (canceled)
 55. (canceled)
 56. (canceled)57. The process of claim 30, further comprising placing a seal-coat overthe core, wherein the seal-coat comprises hydrophilic polymers.
 58. Aprocess for preparing a bilayered, solid, orally administeredpharmaceutical dosage form of a biguanide and a glitazone, the processcomprising: a. dispersing the biguanide in an extended release carrierbase material; b. separately dispersing the glitazone in an immediaterelease carrier base material; and c. compressing the material of step aand step b to form bilayered tablet.
 59. The process of claim 58,wherein the immediate release carrier base material further comprisesone or more wetting agents before or after dispersing the glitazone. 60.The process of claim 59, wherein the glitazone and the one or morewetting agents are present in a weight ratio ranging from about 10:1 toabout 1:25.
 61. (canceled)
 62. (canceled)
 63. (canceled)
 64. (canceled)65. (canceled)
 66. (canceled)
 67. (canceled)
 68. (canceled) 69.(canceled)
 70. (canceled)
 71. (canceled)
 72. (canceled)
 73. (canceled)74. (canceled)
 75. (canceled)
 76. (canceled)
 77. (canceled) 78.(canceled)
 79. (canceled)
 80. (canceled)
 81. (canceled)
 82. (canceled)83. (canceled)
 84. (canceled)
 85. (canceled)
 86. A method of treatingnon-insulin dependent diabetes mellitus in a patient in need thereof,the method comprising administering a solid, pharmaceutical dosage formof the combination of a biguanide and a glitazone, wherein the dosageform provides an extended-release of the biguanide and an immediaterelease of the glitazone.
 87. The method of claim 86, wherein thebiguanide comprises one or more of metformin, phenformin, and buformin.88. (canceled)
 89. The method of claim 86, wherein the glitazonecomprises one or more of pioglitazone, rosiglitazone, troglitazone,ciglitazone and englitazone.
 90. (canceled)
 91. The method of claim 86,wherein after oral administration the biguanide is released over aperiod of about 4 to about 36 hours.
 92. The method of claim 86, whereinthe biguanide is released over a period of about 8 to about 24 hours.93. (canceled)
 94. The method of claim 86, wherein the dosage formfurther comprises one or more of sulfonylurea, insulin,alpha-glucosidase inhibitors, meglitinides, fibrates, statins, squalenesynthesis inhibitors and angiotensin-converting enzyme inhibitors.